Norepinephrine (NE) is known to play a role in plasticity in the brain, however the exact mechanism by which NE acts is still under investigation. A clear understanding of the role of NE in plasticity in the cerebellum would help us in understanding diseases where catecholamine imbalances occur and in aging where NE signal transduction is altered. Our working hypothesis is that release of NE in the cerebellum during learning activates the beta-noradrenergic receptor signal transduction cascade and this activation is critical for cerebellar motor learning. Behavioral studies from our lab and others have shown that NE in the cerebellum modulates the rate of acquisition of various motor learning tasks including classical eyelid conditioning. Studies in animal models from fruit flies, bees, and Aplysia, to mice and rats indicate a growing convergence of information regarding signal transduction cascades involved in learning and memory, including the clear implication of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) in both long and short-term memory formation in numerous parts of the brain. Less is known, however, regarding how PKA or any other signal transduction molecules contribute to learning in the cerebellum. We have recently determined that localized blockade of b-adrenergic receptors or PKA in the cerebellum causes a significant deficit in acquisition of eyelid classical conditioning. This result has lead us to our current interest in this sparsely studied aspect of cerebellar function. In this application we combine pharmacological, neurochemical and neuroanatomical approaches with behavioral testing. This powerful multifaceted approach will allow us to dissect the varying roles of signaling molecules in cerebellar motor learning. Our research projects will focus on the behavioral paradigm of classical eyelid conditioning. Specific Objective 1: Hypothesis: NE is released in the cerebellar cortex during training on a delay eyelid classical conditioning task and blockade of NE release will disrupt acquisition of CR's but will not disrupt performance of learned CR's. Specific Objective 2: Hypothesis: Cerebellar NE signal transduction (specifically PKA) is necessary for learning of delay eyelid classical conditioning. Specific Objective 3: Hypothesis: NE and PKA lead to significant downstream alterations in signaling molecules.